Although repeated studies have established that bright light is an effective treatment for SAD, the mechanism of its actions remains unknown, as do the fundamental biological abnormalities responsible for the syndrome. There is ample reason to believe that brain serotonergic systems may be involved in these processes. In the past, we undertook preliminary studies to investigate whether SAD patients would respond differently from normal controls to infusions of the somewhat selective serotonin agonist, m-chlorophenylpiperazine (m-CPP). We found that when untreated during the winter months, SAD patients reported being activated to a greater degree than normal controls following the infusion. Effective light treatment or the advent of summer were associated with a normalization of this activation response. Our earlier studies suffered from certain methodological deficiencies. In the present study we have attempted to obviate these deficiencies by increasing our sample size, including a placebo infusion condition and randomly ordering treated, "on lights," and untreated, "off lights", conditions. Seventeen patients who met criteria for winter SAD and 15 healthy controls underwent infusions of either m-CPP or placebo on separate days in both "off lights" and "on-lights", conditions. The "on-lights" condition consisted of 2 weeks of daily treatments with 10,000 lux of white light for 45 minutes in the morning and 45 minutes in the evening; the "off-lights" condition consisted of at least two weeks without any light treatment. Infusions consisted of either 0.08 mg/kg of m-CPP in normal saline or the saline alone. At baseline and for 90 minutes following the infusion, we measured behavior by means of a 24-item NIMH self-rating scale, body temperature, and drew blood for hormonal measurements. As we had found previously, the "activation-euphoria" subscore increased significantly in SAD patients during the "off lights" condition, as compared with the "on-lights" condition or with the normal controls under either condition (F=4.7; df = 3, 90; Greenhouse-Geisser corrected P is less than .O5) . Increase in activation following m-CPP infusions in patients in the "off-lights" condition correlated significantly with antidepressant response to light, as measured by the Hamilton Depression Rating Scale. We therefore replicated and strengthened our earlier finding. Serotonergic abnormalities appear to related to the pathophysiology of SAD and its response to light.